(a) Field of the Invention
The present invention relates to imidazole-1-yl pyrimidine derivatives or a pharmaceutically acceptable salts thereof, and a pharmaceutic composition comprising the same as an active ingredient.
(b) Description of the Related Art
In spite of profound progress in cancer researches over the years, it is still the second leading cause of death worldwide. Extensive studies of the molecular mechanism of cancer have revealed many specific molecular targets for its therapy. In fact, the targeted cancer therapy has been very successful, particularly, in the case of kinase inhibitors. Protein kinases are involved in various cell signaling pathways including cell cycle regulation, apoptosis, and proliferation, and the dysregulation of specific protein kinases has been implicated in several cancers.
For example, in the case of melanoma, MAPK (mitogen-activated protein kinase; RAS-RAF-MEK-ERK) and PI3K-AKR (phosphoinositide 3-kinase-AKT) pathways are upregulated and alternation of the signaling through both the pathways plays a major role in melanoma progression.
Since the findings that about 70% of melanoma have V600E mutant, there have been significant amounts of small molecule inhibitors developed, which target BRAF V600E.
The recent success of Vemurafenib shows the importance of selective BRAF V600E inhibitor. Furthermore, there is a significant portion of melanomas (>33%) not including BRAF V600E mutations, which will require alternative therapy targets. CRAF (or RAF1) gene which is closely related to BRAF, is involved in abnormal proliferation of melanoma. Similar to BRAF, CRAF is involved in activating of a MAPK signal transduction system, but, unlike BRAF, CRAF controls lower proteins such as MST (STK3) and ASK1 (MAP3K5), independent of the MAPK signal transduction system.
Moreover, CRAF affects mitochondria directly, thereby controlling the inhibition of apoptosis, which is achieved via phosphorylation of BAD through direct coupling with BCL2. CRAF seems to be related with mutants of NRAS. A recent study, which shows that BRAF can directly phosphorylate CRAF, emphasizes the value of CRAF as a target protein for melanoma therapeutics. Therefore, the development of potent and selective CRAF inhibitors, as well as BRAF V600E inhibitors, would be ideal for melanoma treatment.
Known protein kinase inhibitors can be classified into type I and type II, depending on the conformational state of the kinase with the inhibitors bound. The type I inhibitors bind to the ATP-binding site through the formation of hydrogen bonds at the hinge region. Meanwhile, the type II inhibitor bind to the ATP-binding site, but also occupy the unique secondary hydrophobic pocket in the inactive conformation of the kinase domain. In this respect, the approach to the type II inhibitors may be stronger for the selective protein kinase inhibitor.